Kaposi's Sarcoma (KS) is the most common neoplasm in AIDS patients affecting approximately 20 percent of HIV infected individuals. While HIV-1 is neither necessary nor sufficient for the development of KS, AIDS-KS is recognized as more aggressive, disseminated and resistant to treatment that other forms of this disease. Recent studies have identified a new human herpesvirus, HHV-8, in virtually 100 percent of KS lesions. While it appears that HHV-8 is essential to the development of KS, it is currently unclear what additional co-factors are responsible for the aggressive nature of AIDS-KS. It is often assumed that induction of immunosuppression in AIDS allows for the replication of HHV-8 and development of KS by suppression of anti-viral and immunosurveillance mechanisms. However, immunosuppression alone can not explain the overwhelming prevalence of KS in AIDS patients in comparison with other immunosuppressed patient populations, the almost exclusive development of KS in patients infected with HIV-1, but not HIV-2, or the frequent occurrence of KS early in AIDS prior to the development of immunosuppression. In this proposal, we hypothesize that a molecular interaction occurs between HIV-1 and HHV-8. HIV-1 related proteins and/or cytokines released from HIV-1 infected cells reactivate HHV-8 from latency resulting in an increased viral load and, therefore, contributing to the high frequency and aggressive nature of AIDS- KS. The proposed studies will not only characterize the interaction between these two viruses but also identify the viral and/or cellular factors involved in induction of viral replication. We will then extend this in vitro data and examine viral interactions between HIV-1 and HHV-8 in an in vivo model composed entirely of human constituents. By completing these three aims over the next three years, we will gain new insight into the molecular mechanisms governing regulation of HHV-8 and HIV-1 viral replication both in vitro and in vivo Determining essential co-factors that are critical for HHV-8 to cause KS, such as HIV-1, will also facilitate development of experimental animal models to further investigate this disease. Such models will be particularly useful for devising new therapies for AIDS- KS.